Clinical and genetic correlations of familial Hirschsprung's disease

J Pediatr Surg. 2015 Feb;50(2):285-8. doi: 10.1016/j.jpedsurg.2014.11.016. Epub 2014 Nov 7.


Background: The risk of familial transmission in Hirschsprung's disease (HSCR) currently lacks correlation between the clinical phenotype and the underlying genetic factors. The aim of this study was to clinically evaluate familial HSCR transmission and to correlate with the genetic background.

Methods: Clinical and gene analysis of familial HSCR patients were explored. DNA from 45 patients (35 kindreds) was screened for genetic variations of the RET, and EDNRB genes were screened for genetic variation by semi-automated bi-directional sequencing analysis and matched to controls.

Main results: Male:female ratio (3:1) had a female proband in 4 families. Aganglionosis was significantly more frequent with total colonic aganglionosis (TCA) in 40% familial cases (viz: 17/43 (43%) vs. 19/342 non-familial patients (5.6%) (p<0.01)). Transmission of S-HSCR was observed in 13 (31%), which was associated with EDNRB variation. RET gene promoter variation correlated with extended aganglionosis in 6/35 kindreds (17%). In 3 kindreds, both significant EDNRB and RET mutations were identified and where present were associated with increased penetrance in succeeding generations. An increased penetrance with succeeding generations occurred in 6 (14%). In a further 3 generation family, extensive variations in exon 6, 13, and 18 affected 3 males with progressive penetration and aganglionic length, including total intestinal aganglionosis in the further offspring. RET and MEN association was noted in 5 kindreds (14.3%) related to RET variations at Cysteine sites.

Conclusions: Cumulative effects of the RET and EDNRB genes contribute to long-segment and total colonic aganglionosis.

Keywords: EDNRB gene; Familial; Genetic RET protooncogene; Hirschsprung’s disease.

MeSH terms

  • Child
  • DNA / genetics*
  • DNA Mutational Analysis
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Hirschsprung Disease / genetics*
  • Humans
  • Male
  • Mutation*
  • Pedigree
  • Phenotype
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-ret / genetics*
  • Receptor, Endothelin B / genetics*


  • EDNRB protein, human
  • Receptor, Endothelin B
  • DNA
  • Proto-Oncogene Proteins c-ret
  • RET protein, human

Supplementary concepts

  • Aganglionosis, total intestinal